It is proposed to continue studies in rat and human tissue concerned with the disposition of the volatile anesthetics, halothane, methoxyflurane, isoflurance, and enflurance. Recent studies of halothane in our laboratory indicate that a metabolite of it initially binds irreversibly to phospholipids and later it is bound to protein. We plan to pursue the study of this binding to determine if this is unique to halothane and whether this binding plays a role in the hepatotoxicity sometimes seen following the use of this agent. Our studies of methoxyflurane indicate that an acid-labile metabolite is produced in high concentration and when this metabolite breaks down, large amounts of inorganic fluoride are released. Thus, this metabolite may play a key role in the nephrotoxicity sometimes seen following the methoxyflurane anesthesia. Studies are planned to determine if this acid-labile metabolite breaks down in the kidneys and whether this can be controlled and thereby control the toxicity. Isoflurance and enflurane are halogenated anesthetics recently made available for clinical use. We propose to study the disposition of these agents in detail using the same techniques as those developed for the studies of halothane and methoxyflurane. In addition to studying the disposition of these agents in hepatic tissue, studies will also be conduced in lung and kidney tissue. The studies in lung tissue will include both lung perfusion and in vitro in subcellular fractions. Guided by the results of the animal studies we plan to pursue these investigations in human hepatic tissue obtained at autopsy.